[unreadable] [unreadable] Current strategies for chemoprevention and adjuvant therapy for treating women at high risk for estrogen receptor-positive breast cancer rely predominantly on anti-estrogen therapy. These therapies have been successful, however, they have show that anti-estrogen therapy is not effective in all patients and may have limited duration of efficacy. As combination therapy has been shown to be effective for treating invasive carcinomas, the use of combination therapy may offer improved efficacy and duration for chemoprevention. We hypothesize that dual agent therapy that targets complementary processes (e.g. cell death and proliferation) or complementary pathways will lead to improved therapeutic efficacy and have a potential to eradicate preneoplastic disease. Our plan is to test this hypothesis on a mouse model that that our group has developed that mimics human ductal carcinoma in situ (DCIS), or high risk preneoplastic breast lesions. For this approach, we have chosen to use tamoxifen, a SERM that we have shown to decrease tumor incidence and affect proliferation in our mouse model, in combination with rapamycin, an mTOR inhibitor that also decreases tumor incidence but affects apoptosis in our mouse model. We expect that these two agents, which are each effective in reducing but not eliminating the preneoplastic growth and tumor incidence, with their complementary mechanisms of action will provide a statistically significant improved decrease in the preneoplastic tissue growth and tumor incidence as compared to each agent alone. In a second approach, we believe that targeting pathways that provide the preneoplastic or tumor lesions the ability to survive during and after therapeutic treatment are excellent targets for combination therapy. In rapamycin treatment, we have identified one of these potential survival genes/pathways. By targeting this gene, PPARg, we believe we can potentially improve the efficacy of rapamycin treatment by inhibiting this compensatory mechanism. Therefore, we believe that these combinational therapies, in one case using modulators of proliferation and apoptosis, and in another case by targeting a cell survival pathway specific to one of the agents, can provide improved clinical efficacy. The studies described in this application are highly significant, as they will be able to directly test our hypothesis in one of the only models that mimics the human DCIS. If our hypothesis is affirmed, these data may be the basis for new adjuvant and therapeutic regimes to be initiated in women at risk for breast cancer or breast cancer recurrence. With the potential of improved efficacy and reduced toxicity over current treatment, these studies will make decided progress toward our goal of the complete eradication of preneoplastic breast disease. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]